Racemic and asymmetric cobalt-catalysed reductive aldol couplings of α,β-unsaturated amides with ketones

Article abstract of DOI:10.1016/j.tet.2008.06.022

In the presence of diethylzinc as a stoichiometric reductant, substoichiometric quantities of an appropriate cobalt source catalyse diastereoselective reductive aldol coupling reactions of α,β-unsaturated amides with ketones. The use of a readily available oxazolidine as a chiral auxiliary imparts high levels of asymmetric induction in these reactions.

Full text of DOI:10.1016/j.tet.2008.06.022

Tetrahedron 64 (2008) 7729–7740
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Racemic and asymmetric cobalt-catalysed reductive aldol
couplings of
a,
b-unsaturated amides with ketones
*
Ralph J.R. Lumby, Pekka M. Joensuu, Hon Wai Lam
School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of diethylzinc as a stoichiometric reductant, substoichiometric quantities of an appro-
Received 27 March 2008
Received in revised form 15 May 2008
Accepted 5 June 2008
priate cobalt source catalyse diastereoselective reductive aldol coupling reactions of
amides with ketones. The use of a readily available oxazolidine as a chiral auxiliary imparts high levels of
asymmetric induction in these reactions.
a,b-unsaturated
Available online 10 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
lactams3a,4,6b using reductive aldol cyclisations, we recently
established the exceptional ability of Co(acac)2$2H2O/Et2Zn3a in
The reductive aldol reaction, in which an aldehyde or ketone
undergoes reaction with an enolate generated in situ by the con-
promoting reactions of substrates that were problematic under
previously reported conditions using copper catalysis6 (represen-
tative example in Eq. 1).
jugate reduction of an
a,b-unsaturated carbonyl compound, is
a powerful and well-established method of carbon–carbon bond
formation.1,2 Using various metal precatalysts and stoichiometric
reductants that include silanes, triethylborane and molecular hy-
drogen, a wide variety of inter- and intramolecular reductive aldol
reactions have been described.1,2 A recent major development in
this area is the ability to control the absolute stereochemistry of the
products through the use of substoichiometric quantities of chiral
metal–ligand complexes.2
One contribution to this field from our research group has been
the development of both inter- and intramolecular reductive aldol
reactions that employ diethylzinc as the stoichiometric reductant, in
conjunction with cobalt3 or nickel4 precatalysts. An advantageous
feature of these conditions is the ability to promote high-yielding
Et2Zn (2 equiv)
Co(acac)2·2H2O
(0.5 mol %)
O
O
O
PMP
Ph
Me
HO
N
Ph
N
PMP
Me
ð1Þ
THF, hexane, 0 °C
2
1
1.62 g
1.28 g (79%)
>19:1 dr
Whether the Co(acac)2$2H2O/Et2Zn combination could also be
applied to the corresponding intermolecular reductive aldol re-
actions was an important issue to address, and with this consid-
eration in mind, the reaction of N,N-dimethylacrylamide (3) with
acetophenone was conducted. This experiment was successful, and
provided the aldol product 4a7 in 75% yield, accompanied by the
diastereomeric product (not shown), in a 5:1 ratio (Table 1, entry 1).
The use of 4-acryloylmorpholine (6) as the pronucleophilic com-
ponent provided very similar results (Table 2, entry 1).
Further examination of substrate scope revealed that aceto-
phenone derivatives containing alkyl, methoxy or bromo sub-
stituents were competent electrophiles in these reactions,
providing tertiary alcohol-containing aldol products with up to 9:1
diastereomeric ratio and 85% isolated yield of the major di-
astereomer (Table 1, entries 2–6 and Table 2, entries 1–3). ortho-
Substitution in the acetophenone was found to result in enhanced
levels of diastereoselection (Table 1, entries 2 and 5 and Table 2,
entry 2). However, the reaction of 4-nitroacetophenone with 3
provided none of the desired product 4g, with a complex mixture
being obtained instead (Table 1, entry 7). Presumably, the highly
electron-deficient nature of this particular ketone leads to delete-
rious side reactions under these conditions. Other aromatic
reactions between
b-substituted a,b-unsaturated carboxylic acid
derivatives and ketones, reaction partners that are situated on the
lower end of the reactivity scale in reductive aldol reactions. In this
article, we provide a full account of the intermolecular reactions3b
promoted by Et2Zn in combination with a cobalt source,5 along with
extension to an asymmetric variant using a chiral oxazolidine
auxiliary.
2. Results and discussion
During ongoing efforts to develop new catalyst systems for the
diastereoselective synthesis of
b
-hydroxylactones4,6a and
* Corresponding author. Tel.: þ44 131 650 4831; fax: þ44 131 650 6453.
E-mail address: h.lam@ed.ac.uk (H.W. Lam).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.022

7730
R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
Table 1
Table 3
Cobalt-catalysed reductive aldol reactions of N,N-dimethylacrylamide (3) with
Cobalt-catalysed reductive aldol reactions of acetophenone with representative
unsaturated morpholine amidesa
a,b-
representative ketonesa
Et2Zn (2 equiv)
Co(acac)2·2H2O
Co (cat.)
O
Me OH
Ph
O
ligand (cat.)
O
O
O
O
Me OH
R
(5 mol %)
Et2Zn (2 equiv)
Me
Me
N
+
N
R
+
Me
Ph
N
Me
R
N
THF, hexane, 0 °C
THF, hexane
0 °C to rt
O
O
Me
Me Me
4
R
3
9a-9f
10a-10f
Method A: Co(acac)2·2H2O (5 mol %)
Method B: CoCl2 (5 mol %), Cy2PPh (5.5 mol %)
+ diastereomer 5
Entry
R
Product(s)
drb
5:1
9:1
5.5:1
6:1
Yield(s)c (%)
Entry
Method
R
Substrate
Product
drb
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
Ph
2-MePh
4-MePh
4-MeOPh
2-BrPh
4-BrPh
4-NO2Ph
2-Naphthyl
2-Furyl
4a
4b
4c
4d
4e
4f, 5f
4g
4h
4i, 5i
4j
75
68
79
1
2
3
4
5
6
B
B
B
A
A
A
Me
i-Bu
CH2CH2Ph
Ph
2-Naphthyl
2-Furyl
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
>19:1
>19:1
16:1
>19:1
10:1
76
85
81d
71
84
7:1
56
3.5:1
n/a
73 (15)
0d
74
84
9:1
5:1
78
a
Reactions were conducted using 1.0 mmol of 9a–9f and 1.1 mmol of acetophe-
2.5:1
n/a
66 (25)
0d
none in THF (10 mL) and hexane (2 mL) for 2–6 h.
CO2Et
Determined by 1H NMR analysis of the unpurified reaction mixtures.
b
a
c
Reactions were conducted using 1.0 mmol of 3 and 1.1 mmol of ketone in THF
Isolated yield of major diastereomer.
Yield of a 16:1 inseparable mixture of diastereomers.
d
(10 mL) and hexane (2 mL) for 1–29 h.
Determined by 1H NMR analysis of the unpurified reaction mixtures.
Isolated yield of major diastereomer; numbers in parentheses refer to yields of
b
c
conditions, substrates containing aromatic (entries 4 and 5) or
heteroaromatic (entry 6) groups also provided good results.
minor diastereomers if isolated.
d
A complex mixture of unidentified products was obtained.
Although a,b-unsaturated esters such as tert-butyl acrylate and
methyl cinnamate also underwent successful reaction with aceto-
phenone under these conditions, they provided the products as ca.
1:1 mixtures of diastereoisomers. Therefore, the reaction of sub-
strate 11 was of interest, since there is the potential to generate
Table 2
Cobalt-catalysed reductive aldol reactions of 4-acryloylmorpholine (6) with repre-
sentative ketonesa
Et2Zn (2 equiv)
R1 OH
R2
O
O
Co(acac)2·2H2O
(5 mol %)
O
products of reductive aldol coupling a- to the ester, as well as a- to
+
N
N
the amide. In the event, reaction of 11 with a range of methyl ke-
tones provided only lactones 13a–13c, formed through cyclisation
of the intermediate zinc alkoxides 12 onto the pendant ethyl ester,
in 62–68% yield (Scheme 1). These experiments demonstrate the
high chemoselectivity for generation of amide enolates rather than
ester enolates under these conditions.
R1
R2
THF, hexane, 0 °C
O
O
Me
6
7
+ diastereomer 8
Entry
R1
R2
Ph
Product(s)
drb
5.5:1
9:1
6.5:1
4.5:1
3:1
Yield(s)c (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Et
7a
7b
7c
7d, 8d
7e, 8e
7f, 8f
7g, 8g
7h
80
84
85
2-MePh
4-MeOPh
2-Naphthyl
2-Furyl
i-Pr
Et2Zn (2 equiv)
O
Me
82 (17)
72 (22)
33 (31)
35 (36)
75
O
Co(acac)2·2H2O
(5 mol %)
R
N
N
CO2Et
O
1:1
1:1
6:1
THF, hexane
0 ºC to rt
O
11
O
i-Bu
O
dr >10:1 O
Ph
Ph
Ph
7i
n/a
62
+
O
13a R = Ph, 68%
13b R = 4-MeOPh, 62%
13c R = 2-naphthyl, 65%
Me
OZnEt
R
Me
R
a
Reactions were conducted using 1.0 mmol of 6 and 1.1 mmol of ketone in THF
N
(10 mL) and hexane (2 mL) for 3–7 h.
b
Determined by 1H NMR analysis of the unpurified reaction mixtures.
Isolated yield of major diastereomer; numbers in parentheses refer to yields of
O
CO2Et
c
12
minor diastereomers if isolated.
Scheme 1. Formation of lactones 13a–13c via reductive aldol coupling of 11.
ketones, such as those containing naphthyl or furyl substituents
(Table 1, entries 8 and 9 and Table 2, entries 4 and 5), propiophenone
(Table 2, entry 8) and benzophenone (Table 2, entry 9), were also
tolerated. Aliphatic ketones also proved to be viable substrates in
these reactions (Table 2, entries 6 and 7). However, no diaster-
eoselection was observed in these cases, and both diastereomeric
products were isolated in comparable yields. The reaction of ethyl
pyruvate with 3 provided only a complex mixture (Table 1, entry 10).
Next, using acetophenone as the electrophile, a study of the
Attempts to extend the scope of these reactions by using a-
substituted
a,b-unsaturated amides such as 4-methacryloyl mor-
pholine were unsuccessful, providing only complex mixtures.
X-ray crystal structures of aldol products 4d, 7f and 7g allowed
determination of their relative stereochemistry8 (Fig. 1), and the
relative configurations of the remaining products in Tables 1–3 and
Scheme 1 were assigned by analogy.
Our current working model for the mechanism of these re-
actions9 is presented in Scheme 2, and involves the participation of
effect of substitution at the
component was carried out (Table 3). These reactions proceeded to
b
-carbon of the
a
,
b
-unsaturated amide
p-allylcobalt species. Seminal work by MacKenzie and co-
workers10 along with important contributions by Ogoshi, Kurosawa
and co-workers11 have described the oxidative addition of low-
give aldol products 10a–10f with ꢀ9:1 dr, demonstrating the
beneficial effect of a
b
-substituent on diastereoselectivity. Amides
valent transition metals to
the presence of a suitable Lewis acid to form
plexes. In addition, strong evidence has been provided that such
-allylmetal species are intermediates in Pd-catalysed conjugate
addition reactions of organometallic reagents11a and disilanes.11b
a
,b
-unsaturated carbonyl compounds in
containing linear or branched alkyl groups at the
b-position were
p-allylmetal com-
tolerated (entries 1–3), but the use of an alternative precatalyst
combination of CoCl2 with the electron-rich monophosphine
Cy2PPh was required for complete conversions.3a Under standard
p

R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
7731
O
Me OH
Me
N
Me Me
4d
OMe
O
N
Me OH
Me
O
Me Me
7f
O
Me
Me OH
N
Me
O
Me
7g
Figure 1. X-ray structures of 4d, 7f and 7g.
Given this precedent, we believe that treatment of Co(acac)2
with Et2Zn leads to the formation of a cobalt(I) species that, with
the assistance of additional Et2Zn, binds to the substrate 14, as in 15.
The presence of a three-centre–two-electron bridging interaction
between cobalt, zinc and an ethyl ligand in 15 has precedent in
a detailed study by Schleger, Montgomery and co-workers in re-
lated nickel-catalysed reactions,12 and has been observed crystal-
lographically for cobalt13 and nickel14 complexes involving
Grignard13,14a and organoaluminium14b reagents. From 15, oxida-
would then provide 18, which upon reductive elimination would
give Z-zinc enolate 19 that undergoes aldol reaction with the ke-
tone, along with regeneration of Co(I). In this model, the regio-
chemical outcome of conjugate reduction of 11 (Scheme 1) may be
explained by preferential binding of Et2Zn/Co at the amide carbonyl
rather than the ester carbonyl, due to the greater Lewis basicity of
the amide.
The diastereochemical outcomes of these reactions7,8 may be
explained via the intervention of a chelated chair-like Zimmerman–
Traxler transition state15 in which the larger aromatic substituent of
the ketone prefers to reside in a less sterically hindered pseudoe-
quatorial position (as in TS 2) (Scheme 3), rather than in a pseu-
doaxial position (as in TS 1). The absence of diastereoselectivity
with aliphatic ketones (Table 1, entries 6 and 7) is due presumably
to reduced differences in size between the two substituents at-
tached to the carbonyl group.
tive addition of Co(I) into the
a,b-unsaturated amide along with
transmetalation of an ethyl group from zinc to cobalt would then
generate
p-allylcobalt(III) species 16, that can then undergo b-hy-
dride elimination to give cobalt hydride 17. h3
–
h1 Isomerisation
Co(acac)2
Et2Zn
O
R1
EtZnO
R1
H
N
N
R1
R2
R2
R1
R1
O
R1
14
N
O
Ar OH
R3
19
Ar
R1
LCo(I)
R3
Ar
H
EtZn
+ Et2Zn
O
N
O
R1
R3
R1
R2
minor isomer
20
R1
R2
R1
TS 1
R1
N
OZnEt
EtZnO
H
N
R1
R2
N
R2
R1
R2
O
R1
R1 19
18
R3 OH
Ar
N
O
Co
Zn
Co
15
R3
H
R1
Et
EtZn
L
L
O
N
Et
R1
O
O
R1
Ar
TS 2
R2
major isomer
R3
Ar
R2
21
Et
O
R1
EtZnO
Zn
H
N
H
N
Scheme 3. Model for stereochemical outcome.
R1
R1
R2
17
R2
16
Co
Co
H
L
Et
L
Having demonstrated the general scope of these intermolecular
reductive aldol reactions, we sought to develop an asymmetric
variant of the process. Examination of the literature reveals that
CH2=CH2
Scheme 2. Possible catalytic cycle.

7732
R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
Table 5
compared with the large body of work pertaining to asymmetric
aldol reactions using aldehydes as the electrophiles,16 there are far
fewer examples using ketones.17–19 Factors responsible for this
paucity include the attenuated reactivity of ketones compared with
aldehydes, problems with retroaldolisation and smaller differences
in steric properties between the two substituents attached to the
ketone carbonyl. The latter feature is often manifested in low levels
of diastereoselectivity (such as in Table 1, entries 6 and 7) and
enantiofacial discrimination. Although a number of approaches to
address these challenges have been documented,17–19 there re-
mains room for improvement, since existing procedures often
display suboptimal selectivities or narrow substrate scope. There-
fore, the development of new, complementary methods for con-
ducting asymmetric ketone aldol reactions continues to be
a valuable endeavour.
The prospects of developing a catalytic asymmetric variant of
the reactions described herein through the use of a suitable chiral
cobalt–ligand complex were deemed unpromising, since according
to our mechanistic hypotheses (Schemes 2 and 3), cobalt is not
a participant in the aldol reaction. Indeed, initial trials using sub-
stoichiometric quantities of various chiral ligands did not give rise
to any enantioselection.20 Therefore, we turned to a chiral auxiliary
strategy, and a number of potential candidates were screened for
their ability to give both high reaction efficiencies and high levels of
enolate diastereofacial selectivity. Although N-alkenoylox-
azolidinones seemed an obvious first choice,16a these substrates did
not provide aldol products under our conditions. Fortunately, N-
acryloyloxazolidine 2221 was found to meet our desired criteria,
reacting with acetophenone to afford aldol product 23a in 73% yield
Cobalt-catalysed reductive aldol reactions of acetophenone with representative
N-alkenoyloxazolidinesa
Co (cat.)
Me Me O Me OH
Ph
O
Me
O
Me
N
ligand (cat.)
O
Et2Zn (2 equiv)
THF, hexane
0 °C to rt
R
O
N
+
Me
Ph
24a-24h
R
Ph
Ph
25a-25h
Method A: Co(acac)2·2H2O (5 mol %)
Method B: CoCl2 (5 mol %), Cy2PPh (5.5 mol %)
Entry
Method
R
Substrate
Product
drb,c
16:1
15:1
15:1
>19:1
>19:1
>19:1
>19:1
>19:1
Yieldd (%)
1
2
3
4
5
6
7
8
B
B
B
A
A
A
A
A
Me
i-Pr
CH2CH2Ph
Ph
24a
24b
24c
24d
24e
24f
25a
25b
25c
25d
25e
25f
82
79
80
86
86
84
90
83
4-MeOPh
4-ClPh
2-Naphthyl
2-Furyl
24g
24h
25g
25h
a
Reactions were conducted using 0.5 mmol of 24a–24h and 0.55 mmol of ace-
tophenone in THF (2.5 mL) and hexane (1 mL) for 4–6 h.
b
Determined by 1H NMR analysis of the unpurified reaction mixtures.
c
dr¼(major isomer)/
S
(other isomers).
d
Isolated yield of major diastereomer.
in Table 3, these examples illustrate that substitution at the acryl-
amide has a beneficial effect on reaction diastereoselectivity
(ꢀ15:1). In addition, the reactions of 24a–24h were cleaner than
those of N-acryloyloxazolidine 22, which resulted in higher isolated
yields of products. Once again, the combination of CoCl2 and
Cy2PPh3a was required for complete conversions when acrylamides
24a–24c containing alkyl substitution were employed (entries 1–
3). Aromatic- and heteroaromatic-substituted N-alkenoylox-
azolidines 24d–24h were the best substrates in these reactions,
affording aldol products in 83–90% yield as one observable di-
astereomer (>19:1 by 1H NMR analysis) (entries 4–8).
The yields and diastereoselectivities of these reactions are
maintained on increasing the scale. For example, reaction of cin-
namoyl-substituted oxazolidine 24d with 2-acetonaphthone to
give 26 on 0.5 mmol and 5 mmol scales gave comparable results
(Eq. 2).
and with 11:1 diastereoselectivity [major isomer/S(other iso-
mers)]22 (Table 4, entry 1). Further exploration of ketone scope
revealed that acetophenone derivatives containing substituents of
varying electronic properties were tolerated, giving aldol products
in 58–76% yield and with up to 12:1 diastereoselectivity (entries 2–
6).22 Acryloyloxazolidine 22 also underwent reaction with ketones
bearing naphthyl (entries 7 and 9), heteroaromatic (entry 8) and
ethyl substituents (entry 10). Aliphatic ketones proved to be less
suitable substrates in this reaction, providing what appeared to be
mixtures of all four possible diastereoisomers (entry 9).
Table 5 presents the results of reaction of a range of N-alke-
noyloxazolidines 24a–24h with acetophenone. As seen previously
Et2Zn (2 equiv)
Co(acac)2·2H2O
(5 mol %)
Me
O
O Me OH
Me
N
O
Table 4
Me
24d +
Cobalt-catalysed reductive aldol reactions of N-acryloyloxazolidine 22 with repre-
THF, hexane
0 °C to 45
sentative ketonesa
Ph
Ph
26
Et2Zn (2 equiv)
R1
O
O
Me Me
Co(acac)2·2H2O
(5 mol %)
OH
R2
Me
N
Me
O
O
0.5 mmol scale 91% yield, >19:1 dr
5 mmol scale 90% yield, >19:1 dr
O
+
N
R1
R2
THF, hexane
0 °C to rt
22
Me
23a-23j
ð2Þ
Ph
Ph
The stereochemistries of 23a, 23d and 25f were determined by
X-ray crystallography (Fig. 2),23 and the stereochemistries of the
remaining aldol products in Tables 4 and 5, and of 26 were assigned
by analogy.
To explain the sense of asymmetric induction observed in these
reactions, we suggest that in the Zimmerman–Traxler transition
state,15 the geminal dimethyl groups of the oxazolidine are oriented
anti to the enolate oxygen to minimise unfavourable nonbonding
interactions (Scheme 4). Inspection of alternative transition states
TS 3 and TS 4 reveals that the oxazolidine phenyl substituent suffers
fewer nonbonding interactions in TS 4, which lead to the observed
stereochemistry of the major isomer 29.
Entry
R1
R2
Product
drb,c
Yieldd (%)
1
2
3
4
5
6
7
8
9
10
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
23a
23b
23c
23d
23e
23f
23g
23h
23i
11:1
9:1
12:1
8.5:1
12:1
7:1
13:1
6:1
n/a
73
76
72
72
63
58
75
61
0e
4-MePh
3-MePh
4-MeOPh
4-BrPh
3-ClPh
2-Naphthyl
2-Thienyl
t-Bu
60-MeO-2-naphthyl
23j
6:1
59
a
Reactions were conducted using 1.0 mmol of 22 and 1.1 mmol of ketone in THF
(5 mL) and hexane (2 mL) for 3–17 h.
b
Determined by 1H NMR analysis of the unpurified reaction mixtures.
Obviously, the utility of this chiral auxiliary methodology is
apparent only if the oxazolidine may be cleaved cleanly from the
aldol products in high yield. On the basis of literature precedent,21b
c
dr¼(major isomer)/
S(other isomers).
d
e
Isolated yield of major diastereomer.
A complex mixture was obtained.

R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
7733
O
Me Me
Me OH
O
N
Ph
Me
Ph
23a
O
Me Me
Me OH
O
N
Me
OMe
Ph
23d
O
Me Me
Me OH
Ph
O
N
Ph
25f
Cl
Figure 2. X-ray structures of 23a, 23d and 25f.
we expected this task to be straightforward. However, all of our
efforts have been frustrated by the low reactivity of the amide
carbonyl of these compounds, presumably due to high steric
shielding. For example, attempted reductive cleavage of the oxa-
zolidine from 23a using hydride reagents such as LiBEt3H,21b LAB,24
LiAlH4 or DIBAL resulted in no reaction at low-to-moderate tem-
peratures, or retroaldol fragmentation at elevated temperatures.
The TBS ether of 23a was also inert to these reagents, even under
forcing conditions. Various efforts to protect the tertiary alcohol of
the aldol products with other protecting groups such as MEM or
benzyl ethers were unsuccessful, again presumably due to high
steric hindrance. Finally, attempts at acidic hydrolysis25 of the
oxazolidine of 23a, or efforts to remove the isopropylidine group21b
under various Brønsted or Lewis acidic conditions, were compli-
disfavoured
O
Me
Me
O
2
O
Me Me
HO R
Ar
N
R2
R2
Ar
ZnEt
O
O
N
O
O
R1
Ar
OZnEt
Me Me
Ph
28
R1
TS 3
O
N
R1
27
Me
Me
R2 OH
Ar
O
Me Me
Ph
N
R2
O
N
EtZn
O
O
O
R1
Ar
TS 4
favoured
Ph
29
R2
Ar
R1
cated by elimination of the tertiary alcohol to provide
saturated compounds.
b,g-un-
Scheme 4. Model for asymmetric induction.

7734
R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
3. Conclusion
Products 4–13c in Tables 1–3 and Scheme 1 have been reported
previously.3b
Cobalt-catalysed conjugate reduction of a,b-unsaturated amides
using diethylzinc as the stoichiometric reductant generates zinc
enolates that participate in efficient aldol couplings with ketones,
4.2. Preparation of N-alkenoyloxazolidines 22 and 24a–24h
providing tertiary
substitution at the
ated, and best results in terms of diastereoselectivity are obtained
with aromatic ketones such as acetophenone derivatives. Although
aliphatic ketones were found to undergo the reductive aldol re-
action, their reactions exhibit no diastereoselectivity.
b
b
-hydroxycarbonyl products. A wide range of
-carbon of the -unsaturated amide is toler-
4.2.1. (4R)-2,2-Dimethyl-4-phenyl-3-[(E)-propenoyl]-
oxazolidine (22)
a,b
Prepared according to a previously reported procedure.21a
4.2.2. (4R)-3-Bromoacetyl-2,2-dimethyl-4-phenyloxazolidine (31)
Although a readily accessible N-phenylglycinol-derived chiral
auxiliary was found to impart high levels of asymmetric induction
in these reactions, all attempts to cleave the oxazolidine from the
products have been unsuccessful due to the sterically hindered
nature of the products, coupled with the presence of relatively
sensitive tertiary benzylic alcohols. However, this study has defined
structural features for an auxiliary that gives high levels of asym-
metric induction, and provides useful information that might aid in
the design of improved auxiliaries in future.
O
O
Me Me
NH
Me Me
Br
Br
Br
O
O
N
Na2CO3 (aq)
CH2Cl2, rt
31
30
Ph
Ph
Bromoacetyl bromide (7.2 mL, 82.5 mmol) was added in one
portion to a vigorously stirred mixture of oxazolidine 3021a (9.75 g,
55.0 mmol) in CH2Cl2 (55 mL) and saturated aqueous Na2CO3 so-
lution (220 mL), and the mixture was stirred at room temperature
for 4 h. The reaction was partitioned between saturated aqueous
NaHCO3 solution (100 mL) and CH2Cl2 (100 mL). The aqueous layer
was separated and extracted with CH2Cl2 (3ꢂ100 mL), and the
combined organic layers were dried (MgSO4) and concentrated in
vacuo. Purification of the residue by column chromatography (15%
4. Experimental section
4.1. General
All nonaqueous reactions were carried out under a nitrogen
atmosphere in oven-dried apparatus. CH2Cl2 and THF were dried
and purified by passage through activated alumina columns using
a solvent purification system from www.glasscontoursolventsys-
tems.com. ‘Petrol’ refers to that fraction of light petroleum ether
boiling in the range 40–60 ꢁC. Commercially available CoCl2 was
dried by heating under vacuum until it turned from purple to blue.
All other commercially available reagents were used as-received.
Thin layer chromatography (TLC) was performed on Merck DF-
Alufoilien 60F254 0.2 mm precoated plates. Product spots were
visualised by UV light at 254 nm, and subsequently developed us-
ing potassium permanganate or ceric ammonium molybdate so-
lution as appropriate. Flash column chromatography was carried
EtOAc/hexane) gave the bromoamide 31 (10.14 g, 62%) as a light
21
brown solid. Mp 90–92 ꢁC; [
a
]
ꢃ190 (c 1.00, CHCl3); IR (CHCl3)
D
2985, 1660 (C]O), 1400, 1379, 1255, 1237, 1137, 1066, 844,
702 cmꢃ1 1H NMR (360 MHz, CDCl3)
;
d
7.40–7.36 (2H, m, ArH),
7.34–7.29 (3H, m, ArH), 5.07 (1H, dd, J¼6.6, 2.7 Hz, CH2O), 4.39 (1H,
dd, J¼9.0, 6.6 Hz, CHN), 3.91 (1H, dd, J¼9.0, 2.7 Hz, CH2O), 3.55 (1H,
d, J¼11.0 Hz, CH2Br), 3.44 (1H, d, J¼11.0 Hz, CH2Br), 1.86 (3H, s,
C(CH3)2), 1.63 (3H, s, C(CH3)2); 13C NMR (62.9 MHz, CDCl3)
d 163.7
(C), 140.3 (C), 129.0 (2ꢂCH), 128.1 (CH), 125.6 (2ꢂCH), 96.4 (C), 71.2
(CH2), 61.0 (CH), 29.2 (CH2), 25.0 (CH3), 22.2 (CH3); HRMS (FAB)
79
exact mass calcd for C
298.0444.
H
BrNO2 [MþH]þ: 298.0438, found:
13 17
out using silica gel (Fisher Scientific 60 Å particle size 35–70 mm)
employing the method of Still and co-workers. Melting points were
recorded on a Gallenkamp melting point apparatus and are un-
corrected. Infra-red spectra were recorded on a Jasco FT/IR-460 Plus
instrument as a thin film on sodium chloride plates or as a dilute
solution in CHCl3. 1H NMR spectra were recorded on a Bruker
DPX360 (360 MHz) spectrometer or a Bruker ARX250 (250 MHz)
4.2.3. (4R)-3-Diethylphosphonacetyl-2,2-dimethyl-4-phenyl-
oxazolidine (32)
O
O
Me Me
O
P
Me Me
Br
P(OEt)3
120 °C
OEt
OEt
O
N
O
N
31
32
spectrometer. Chemical shifts (d) are quoted in parts per million
Ph
Ph
(ppm) downfield of tetramethylsilane, using residual protonated
solvent as internal standard (CDCl3 at 7.27 ppm). Abbreviations
used in the description of resonances are: s (singlet), d (doublet), t
(triplet), q (quartet), app (apparent), br (broad). Coupling constants
(J) are quoted to the nearest 0.1 Hz. Proton-decoupled 13C NMR
spectra were recorded on a Bruker DPX360 (90.6 MHz) spectrom-
eter or a Bruker ARX250 (62.9 MHz) spectrometer. Chemical shifts
A stirred solution of the bromoamide 31 (10.40 g, 35.0 mmol) in
triethyl phosphite (70 mL) was heated at 120 ꢁC for 2 h. Excess
triethyl phosphite was removed by distillation to leave phosphonate
21
32 (11.82 g, 95%) as a yellow oil. [
a
]
D
ꢃ114 (c 1.00, CHCl3); IR (film)
2985, 1654 (C]O), 1419, 1392, 1365, 1254, 1052, 1025, 974,
(d
) are quoted in parts per million (ppm) downfield of tetrame-
704 cmꢃ1 1H NMR (360 MHz, CDCl3)
;
d
7.41–7.36 (2H, m, ArH),
thylsilane, using deuterated solvent as internal standard (CDCl3 at
77.0 ppm). Assignments were made using the DEPT sequence with
secondary pulses at 90ꢁ and 135ꢁ. 31P NMR spectra were recorded
7.34–7.29 (3H, m, ArH), 5.39 (1H, dd, J¼6.5, 1.9 Hz, OCH2CHN), 4.40
(1H, dd, J¼8.9, 6.5 Hz, CHN), 4.22–4.05 (4H, m, P(OCH2CH3)2), 3.91
(1H, dd, J¼8.9, 1.9 Hz, OCH2CHN), 2.83 (1H, dd, J¼20.3, 14.2 Hz,
CH2P), 2.61 (1H, dd, J¼23.5,14.2 Hz, CH2P),1.86 (3H, s, C(CH3)2), 1.65
(3H, s, C(CH3)2), 1.37–1.33 (3H, m, CH2CH3), 1.32–1.28 (3H, m,
on a Bruker ARX250 (101.2 MHz) spectrometer. Chemical shifts (d)
are quoted in parts per million (ppm) downfield of H3PO4. High
resolution mass spectra were recorded on a Finnigan MAT 900 XLT
spectrometer using the electrospray (ES) positive ion mode at the
EPSRC National Mass Spectrometry Service Centre, University of
Wales, Swansea, or on a Finnigan MAT 900 XLT spectrometer or
CH2CH3); 13C NMR (62.9 MHz, CDCl3)
d
162.2 (C, d, JP¼5.3 Hz), 140.8
(C), 128.7 (2ꢂCH), 127.6 (CH), 125.8 (2ꢂCH), 95.9 (C), 70.8 (CH2),
62.5 (CH2, d, JP¼6.4 Hz), 61.8 (CH2, d, JP¼6.4 Hz), 60.9 (CH), 35.9
(CH2, d, JP¼130.8 Hz), 25.0 (CH3), 22.3 (CH3), 16.0 (CH3, d,
JP¼5.8 Hz), 15.9 (CH3, d, JP¼5.7 Hz); 31P NMR (101.2 MHz, CDCl3)
a
Kratos MS50TC spectrometer at the School of Chemistry,
University of Edinburgh. Optical rotations were performed on an
Optical Activity POLAAR 20 polarimeter.
d
21.7; HRMS (FAB) exact mass calcd for C17H27NO5P [MþH]þ:
356.1622, found: 356.1627.

R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
7735
4.2.4. Wadsworth–Emmons reactions: general procedure A
time of 16 h and purified by column chromatography (30% EtOAc/
21
A solution of phosphonate 32 (1.42 g, 4.00 mmol) in THF
(15 mL) was added via cannula to a suspension of NaH (60%
dispersion in mineral oil, 160 mg, 4.00 mmol) in THF (15 mL) over
3 min at 0 ꢁC. The mixture was then stirred at room temperature
for 30 min before being cooled to 0 ꢁC. The appropriate aldehyde
(1 equiv) was added dropwise or portionwise over 5 min, and the
mixture was then stirred at room temperature until TLC analysis
showed the reaction to be complete. The reaction was quenched
carefully with saturated aqueous NH4Cl solution (20 mL), fol-
lowed by the addition of Et2O (20 mL). The organic layer was
separated and washed with NH4Cl solution (20 mL) and brine
(20 mL), dried (MgSO4) and concentrated in vacuo. Purification of
the residue by column chromatography (EtOAc/hexane) afforded
the N-alkenoyloxazolidine.
hexane) to give a yellow solid (1.09 g, 76%). Mp 125–127 ꢁC; [
ꢃ382 (c 1.00, CHCl3); IR (CHCl3) 2983, 1649 (C]O), 1511, 1422, 1395,
1304, 1242, 1173, 826, 701 cmꢃ1 1H NMR (360 MHz, CDCl3)
7.55
a]
D
;
d
(1H, d, J¼15.3 Hz, ArCH]), 7.42–7.28 (5H, m, ArH), 7.19 (2H, d,
J¼8.7 Hz, ArH), 6.80 (2H, d, J¼8.7 Hz, ArH), 6.27 (1H, d, J¼15.3 Hz,
ArCH]CH), 5.10 (1H, dd, J¼6.6, 2.6 Hz, CH2O), 4.43 (1H, dd, J¼8.9,
6.6 Hz, CHN), 3.97 (1H, dd, J¼8.9, 2.6 Hz, CH2O), 3.79 (3H, s, OCH3),
1.94 (3H, s, C(CH3)2), 1.75 (3H, s, C(CH3)2); 13C NMR (62.9 MHz,
CDCl3)
d
164.2 (C), 160.8 (C), 141.8 (C), 141.7 (CH), 129.3 (2ꢂCH),
129.0 (2ꢂCH), 127.9 (CH), 127.7 (C), 126.0 (2ꢂCH), 117.8 (CH), 114.1
(2ꢂCH), 96.3 (C), 71.4 (CH2), 61.4 (CH), 55.3 (CH3), 25.4 (CH3), 23.5
(CH3); HRMS (FAB) exact mass calcd for C21H24NO3 [MþH]þ:
338.1751, found: 338.1751.
4.2.10. (4R)-3-[(E)-3-(4-Chlorophenyl)propenoyl]-2,2-dimethyl-4-
phenyloxazolidine (24f)
The title compound was prepared according to general pro-
cedure A from 4-chlorobenzaldehyde (562 mg, 4.00 mmol) for
a reaction time of 16 h and purified by column chromatography
4.2.5. (4R)-3-[(E)-But-2-enoyl]-2,2-dimethyl-4-phenyl-
oxazolidine (24a)
Prepared according to a previously reported procedure.25
4.2.6. (4R)-2,2-Dimethyl-3-[(E)-4-methylpent-2-enoyl]-4-
phenyloxazolidine (24b)
(30% EtOAc/hexane) to give a yellow solid (1.15 g, 84%). Mp 117–
21
119 ꢁC; [
a
]
ꢃ342 (c 1.00, CHCl3); IR (CHCl3) 2984, 1651 (C]O),
D
The title compound was prepared according to general pro-
1568, 1492, 1393, 1301, 1245, 971, 819, 702 cmꢃ1
(360 MHz, CDCl3)
;
1H NMR
cedure A from isobutyraldehyde (363
mL, 4.00 mmol) for a reaction
d
7.53 (1H, d, J¼15.4 Hz, ArCH]), 7.42–7.28 (5H,
time of 5 h and purified by column chromatography (20% EtOAc/
m, ArH), 7.20 (2H, d, J¼8.4 Hz, ArH), 7.12 (2H, d, J¼8.4 Hz, ArH), 6.39
(1H, d, J¼15.4 Hz, ArCH]CH), 5.11 (1H, dd, J¼6.5, 2.6 Hz, CH2O),
4.42 (1H, dd, J¼8.9, 6.5 Hz, CHN), 3.96 (1H, dd, J¼8.9, 2.6 Hz, CH2O),
1.95 (3H, s, C(CH3)2), 1.75 (3H, s, C(CH3)2); 13C NMR (62.9 MHz,
21
hexane) to give a yellow solid (910 mg, 83%). Mp 90–92 ꢁC; [
ꢃ120 (c 1.00, CHCl3); IR (CHCl3) 2961, 1660 (C]O), 1455, 1396, 1361,
1256, 1068, 980, 846, 701 cmꢃ1; 1H NMR (360 MHz, CDCl3)
7.30–
a]
D
d
7.18 (5H, m, ArH), 6.72 (1H, dd, J¼15.1, 6.6 Hz, CH]CHC]O), 5.66
(1H, dd, J¼15.1, 1.2 Hz, CH]CHC]O), 4.95 (1H, dd, J¼6.6, 2.8 Hz,
CH2O), 4.31 (1H, dd, J¼8.9, 6.6 Hz, CHN), 3.84 (1H, dd, J¼8.9, 2.8 Hz,
CH2O), 2.21–2.11 (1H, m, CH(CH3)2), 1.82 (3H, s, C(CH3)2), 1.63 (3H, s,
C(CH3)2), 0.79 (3H, d, J¼6.8 Hz, CH(CH3)2), 0.76 (3H, d, J¼6.8 Hz,
CDCl3) d 163.2 (C), 141.4 (C), 140.2 (CH), 135.1 (C), 133.3 (C), 128.9
(2ꢂCH), 128.6 (4ꢂCH), 127.8 (CH), 125.7 (2ꢂCH), 120.6 (CH), 96.1
(C), 71.2 (CH2), 61.2 (CH), 25.1 (CH3), 23.3 (CH3); HRMS (FAB) exact
35
mass calcd for C
H
ClNO2 [MþH]þ: 342.1256, found: 342.1261.
20 21
CH(CH3)2); 13C NMR (62.9 MHz, CDCl3)
d
163.8 (C), 151.7 (CH), 141.4
4.2.11. (4R)-2,2-Dimethyl-3-[(E)-3-(naphthalen-2-yl)propenoyl]-4-
phenyloxazolidine (24g)
(C), 128.5 (2ꢂCH), 127.3 (CH), 125.7 (2ꢂCH), 120.1 (CH), 95.7 (C),
71.0 (CH2), 61.0 (CH), 30.3 (CH), 25.0 (CH3), 23.2 (CH3), 20.9
(2ꢂCH3); HRMS (FAB) exact mass calcd for C17H24NO2 [MþH]þ:
274.1802, found: 274.1807.
The title compound was prepared according to general pro-
cedure A from 2-naphthaldehyde (625 mg, 4.00 mmol) for a re-
action time of 16 h and purified by column chromatography (30%
EtOAc/hexane) to give a yellow solid (1.09 g, 76%). Mp 131–133 ꢁC;
21
4.2.7. (4R)-2,2-Dimethyl-3-[(E)-5-phenylpent-2-enoyl]-4-
phenyloxazolidine (24c)
[a
]
ꢃ402 (c 1.00, CHCl3); IR (CHCl3) 2984, 1651 (C]O), 1401, 1362,
D
1255, 1239, 1068, 848, 749, 701 cmꢃ1
;
1H NMR (360 MHz, CDCl3)
The title compound was prepared according to general pro-
d
7.83–7.79 (3H, m, ArH), 7.75–7.73 (2H, m, ArH), 7.51–7.43 (6H, m,
cedure A from hydrocinnamaldehyde (527
action time of 5 h and purified by column chromatography (20%
m
L, 4.00 mmol) for a re-
ArCH] and ArH), 7.39–7.31 (2H, m, ArH), 6.56 (1H, d, J¼15.3 Hz,
ArCH]CH), 5.16 (1H, dd, J¼6.6, 2.8 Hz, CH2O), 4.48 (1H, dd, J¼8.9,
6.6 Hz, CHN), 4.03 (1H, dd, J¼8.9, 2.8 Hz, CH2O), 2.03 (3H, s,
21
EtOAc/hexane) to give a yellow oil (1.12 g, 83%). [
CHCl3); IR (CHCl3) 2983, 1660 (C]O), 1495, 1375, 1252, 1141, 1068,
848, 735, 700 cmꢃ1; 1H NMR (360 MHz, CDCl3)
7.40–7.16 (8H, m,
ArH), 7.08 (2H, d, J¼7.1 Hz, ArH), 6.88 (1H, dt, J¼14.9, 6.9 Hz,
CH]CHC]O), 5.79 (1H, d, J¼14.9 Hz, CH]CHC]O), 4.93 (1H, dd,
J¼6.5, 2.4 Hz, CH2O), 4.38 (1H, dd, J¼8.9, 6.5 Hz, CHN), 3.93 (1H, dd,
J¼8.9, 2.4 Hz, CH2O), 2.65–2.51 (2H, m, CH2Ph), 2.39–2.28 (2H, m,
CH2CH2Ph), 1.90 (3H, s, C(CH3)2), 1.71 (3H, s, C(CH3)2); 13C NMR
a
]
ꢃ98.0 (c 1.00,
D
C(CH3)2), 1.84 (3H, s, C(CH3)2); 13C NMR (62.9 MHz, CDCl3)
d 163.8
d
(C), 141.8 (CH), 141.7 (C), 133.7 (C), 133.1 (C), 132.4 (C), 129.2 (CH),
129.0 (2ꢂCH), 128.3 (3ꢂCH), 127.9 (CH), 127.5 (CH), 126.8 (CH),
126.4 (CH), 125.9 (2ꢂCH), 123.3 (CH), 120.4 (CH), 96.3 (C), 71.3
(CH2), 61.4 (CH), 25.3 (CH3), 23.5 (CH3); HRMS (FAB) exact mass
calcd for C24H24NO2 [MþH]þ: 358.1802, found: 358.1807.
(62.9 MHz, CDCl3)
d
163.8 (C), 144.8 (CH), 141.5 (C), 140.9 (C), 128.8
4.2.12. (4R)-3-[(E)-3-(Furan-2-yl)propenoyl]-2,2-dimethyl-4-
phenyloxazolidine (24h)
(2ꢂCH), 128.3 (2ꢂCH), 128.2 (2ꢂCH), 127.7 (CH), 125.9 (3ꢂCH),
123.5 (CH), 96.1 (C), 71.3 (CH2), 61.2 (CH), 34.2 (CH2), 33.6 (CH2),
25.3 (CH3), 23.4 (CH3); HRMS (FAB) exact mass calcd for C22H26NO2
[MþH]þ: 336.1959, found: 336.1966.
The title compound was prepared according to general pro-
cedure A from 2-furaldehyde (331
mL, 4.00 mmol) for a reaction
time of 5 h and purified by column chromatography (20% EtOAc/
21
hexane) to give a light yellow solid (1.02 g, 84%). Mp 94–96 ꢁC; [
ꢃ384 (c 1.00, CHCl3); IR (CHCl3) 2985, 1651 (C]O),1557, 1484, 1392,
1246, 1067, 974, 746, 701 cmꢃ1 1H NMR (360 MHz, CDCl3)
7.40–
a]
D
4.2.8. (4R)-2,2-Dimethyl-4-phenyl-3-[(E)-3-phenyl-
propenoyl]oxazolidine (24d)
;
d
Prepared according to a previously reported procedure.25
7.33 (5H, m), 7.30–7.23 (2H, m, ArH, CH]CHC]O and CH), 6.41 (1H,
d, J¼3.3 Hz, CH), 6.36–6.30 (2H, m, CH]CHC]O and CH), 5.09
(1H, dd, J¼6.4, 2.1 Hz, CH2O), 4.38 (1H, dd, J¼8.9, 6.4 Hz, CHN), 3.94
(1H, dd, J¼8.9, 2.1 Hz, CH2O), 1.93 (3H, s, C(CH3)2), 1.73 (3H, s,
4.2.9. (4R)-3-[(E)-3-(4-Methoxyphenyl)propenoyl]-2,2-dimethyl-4-
phenyloxazolidine (24e)
The title compound was prepared according to general pro-
C(CH3)2); 13C NMR (62.9 MHz, CDCl3)
d 163.4 (C), 151.1 (C), 143.8
cedure A from p-anisaldehyde (489
mL, 4.00 mmol) for a reaction
(CH), 141.5 (C), 128.7 (2ꢂCH), 128.5 (CH), 127.5 (CH), 125.7 (2ꢂCH),

7736
R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
117.4 (CH), 113.7 (CH), 111.8 (CH), 96.0 (C), 71.1 (CH2), 60.9 (CH), 25.2
(CH3), 23.1 (CH3); HRMS (FAB) exact mass calcd for C18H20NO3
[MþH]þ: 298.1438, found: 298.1443.
a reaction time of 17 h and purified by column chromatography (5%
EtOAc/petrol) to give a white solid (278 mg, 72%). Mp 95–97 ꢁC;
21
[a
]
ꢃ199 (c 1.00, CHCl3); IR (CHCl3) 3398 (OH), 2980, 2933, 2878,
D
1624 (C]O), 1419, 1302, 1066, 845, 705 cmꢃ1
;
1H NMR (360 MHz,
4.3. Cobalt-catalysed reductive aldol reactions of N-
acryloyloxazolidine 22 with various ketones: general
procedure B
CDCl3) 7.54–7.49 (2H, m, ArH), 7.47–7.43 (3H, m, ArH), 7.09 (1H, t,
d
J¼7.7 Hz, ArH), 6.96 (1H, d, J¼7.7 Hz, ArH), 6.75–6.73 (2H, m, ArH),
5.41 (1H, s, OH), 4.78 (1H, dd, J¼6.6, 2.2 Hz, CH2O), 4.41 (1H, dd,
J¼9.1, 6.6 Hz, CHN), 3.98 (1H, dd, J¼9.1, 2.2 Hz, CH2O), 2.61 (1H, q,
J¼7.1 Hz, CH3CH), 2.28 (3H, s, ArCH3), 1.99 (3H, s, C(CH3)2), 1.67 (3H,
A solution of N-alkenoyloxazolidine 22 (231 mg, 1.00 mmol), the
appropriate ketone (1.10 mmol) and Co(acac)2$2H2O (12.9 mg,
0.05 mmol) in THF (5.0 mL) was stirred at room temperature for
10 min. The mixture was cooled to 0 ꢁC and Et2Zn (1 M solution in
hexane, 2.00 mL, 2.00 mmol) was then added dropwise over 1 min.
The reaction was stirred at 0 ꢁC for 15 min and then at room tem-
perature until complete consumption of the N-alkenoyloxazolidine
as observed by TLC analysis. The reaction was quenched carefully
with saturated aqueous NH4Cl solution (30 mL) and the mixturewas
then extracted with CH2Cl2 (3ꢂ30 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuo. Purification of the
residue by column chromatography afforded the aldol product.
s, C(CH3)2), 0.99 (3H, s, CH3COH), 0.91 (3H, d, J¼7.1 Hz, CH3CH); 13
C
NMR (62.9 MHz, CDCl3)
d 176.2 (C), 145.7 (C), 142.0 (C), 137.2 (C),
129.1 (2ꢂCH), 128.4 (CH), 127.6 (CH), 126.8 (CH), 126.7 (2ꢂCH),
125.2 (CH), 121.5 (CH), 96.1 (C), 74.6 (C), 70.9 (CH2), 61.6 (CH), 46.6
(CH), 29.6 (CH3), 25.5 (CH3), 22.6 (CH3), 21.5 (CH3), 12.1 (CH3);
HRMS (ES) exact mass calcd for C23H30NO3 [MþH]þ: 368.2221,
found: 368.2230.
4.3.4. (4R)-3-[(2R,3R)-3-Hydroxy-3-(4-methoxyphenyl)-2-
methylbutanoyl]-2,2-dimethyl-4-phenyloxazolidine (23d)
The title compound was prepared according to general pro-
cedure B from 40-methoxyacetophenone (165 mg, 1.10 mmol) for
a reaction time of 17 h and purified by column chromatography (5%
EtOAc/petrol) to give a white solid (274 mg, 72%). Recrystallisation
of an EtOAc/hexane solution of 23d at ꢃ20 ꢁC was found to give
4.3.1. (4R)-3-[(2R,3R)-3-Hydroxy-2-methyl-3-phenylbutanoyl]-
2,2-dimethyl-4-phenyloxazolidine (23a)
The title compound was prepared according to general pro-
cedure B from acetophenone (130
m
L,1.10 mmol) for a reaction time
colourless crystals suitable for X-ray diffraction. Mp 183–185 ꢁC;
21
of 16 h and purified bycolumn chromatography (5% EtOAc/petrol) to
give a white solid (257 mg, 73%). Recrystallisation of a CH2Cl2/hex-
[a
]
ꢃ222 (c 1.00, CHCl3); IR (CHCl3) 3366 (OH), 2984, 2971, 2928,
D
1617 (C]O), 1510, 1250, 1177, 1065, 841 cmꢃ1
;
1H NMR (360 MHz,
ane solution of 23a at ꢃ20 ꢁC was found to give colourless crystals
CDCl3) 7.52–7.47 (2H, m, ArH), 7.46–7.42 (3H, m, ArH), 6.85 (2H, d,
d
21
suitable for X-ray diffraction. Mp 215–217 ꢁC; [
a
]
D
ꢃ231 (c 1.00,
J¼8.7 Hz, ArH), 6.75–6.73 (2H, m, ArH), 5.44 (1H, br s, OH), 4.77 (1H,
dd, J¼6.6, 2.1 Hz, CH2O), 4.40 (1H, dd, J¼9.1, 6.6 Hz, CHN), 3.98 (1H,
dd, J¼9.1, 2.1 Hz, CH2O), 3.76 (3H, s, OCH3), 2.54 (1H, q, J¼7.1 Hz,
CH3CH), 1.98 (3H, s, C(CH3)2), 1.66 (3H, s, C(CH3)2), 0.97 (3H, s,
CH3COH), 0.90 (3H, d, J¼7.1 Hz, CH3CH); 13C NMR (62.9 MHz, CDCl3)
CHCl3); IR (CHCl3) 3388 (OH), 2980, 2933, 2878, 1624 (C]O), 1458,
1420, 1065, 765, 702 cmꢃ1 1H NMR (360 MHz, CDCl3)
;
d
7.53–7.48
(2H, m, ArH), 7.47–7.42 (3H, m, ArH); 7.23–7.12 (3H, m, ArH), 6.94
(2H, app d, J¼7.2 Hz, ArH), 5.48 (1H, br s, OH), 4.77 (1H, dd, J¼6.6,
2.2 Hz, CH2O), 4.41 (1H, dd, J¼9.1, 6.6 Hz, CHN), 3.99 (1H, dd, J¼9.1,
2.2 Hz, CH2O), 2.60(1H, q, J¼7.1 Hz, CH3CH),1.98 (3H, s, C(CH3)2),1.67
(3H, s, C(CH3)2), 0.99 (3H, s, CH3COH), 0.90 (3H, d, J¼7.1 Hz, CH3CH);
d
176.3 (C), 157.9 (C), 142.0 (C), 138.0 (C), 129.1 (2ꢂCH), 128.5 (CH),
126.7 (2ꢂCH), 125.6 (2ꢂCH), 113.1 (2ꢂCH), 96.2 (C), 74.4 (C), 71.0
(CH2), 61.6 (CH), 55.1 (CH3), 46.8 (CH), 29.6 (CH3), 25.6 (CH3), 22.7
(CH3), 12.2 (CH3); HRMS (ES) exact mass calcd for C23H30NO4
[MþH]þ: 384.2169, found: 384.2167.
13C NMR (62.9 MHz, CDCl3)
d 176.2 (C), 145.8 (C), 142.0 (C), 129.2
(2ꢂCH), 128.5 (CH), 127.8 (2ꢂCH), 126.7 (2ꢂCH), 126.1 (CH), 124.5
(2ꢂCH), 96.3 (C), 74.6 (C), 71.0 (CH2), 61.6 (CH), 46.7 (CH), 29.6 (CH3),
25.6 (CH3), 22.7 (CH3), 12.2 (CH3); HRMS (ES) exact mass calcd for
4.3.5. (4R)-3-[(2R,3R)-3-(4-Bromophenyl)-3-hydroxy-2-
methylbutanoyl]-2,2-dimethyl-4-phenyloxazolidine (23e)
C
22H28NO3 [MþH]þ: 354.2064, found: 354.2064.
The title compound was prepared according to general pro-
cedure B from 40-bromoacetophenone (219 mg, 1.10 mmol) for
a reaction time of 16 h and purified by column chromatography (5%
4.3.2. (4R)-3-[(2R,3R)-3-Hydroxy-2-methyl-3-(4-methyl-
phenyl)butanoyl]-2,2-dimethyl-4-phenyloxazolidine (23b)
The title compound was prepared according to general pro-
EtOAc/petrol) to give a white solid (273 mg, 63%). Mp 132–134 ꢁC;
21
cedure B from 40-methylacetophenone (155
mL, 1.10 mmol) for
[a
]
ꢃ236 (c 1.00, CHCl3); IR (CHCl3) 3418 (OH), 2981, 2933, 2878,
D
a reaction time of 16 h and purified by column chromatography (5%
1625 (C]O), 1457, 1411, 1066, 840, 703 cmꢃ1
;
1H NMR (360 MHz,
EtOAc/petrol) to give a white solid (280 mg, 76%). Mp 171–173 ꢁC;
CDCl3) 7.52–7.40 (5H, m, ArH), 7.33–7.31 (2H, m, ArH), 6.79 (2H, d,
d
21
[
a]
ꢃ249 (c 1.00, CHCl3); IR (CHCl3) 3398 (OH), 2985, 2932, 1621
J¼8.3 Hz, ArH), 5.48 (1H, s, OH), 4.75 (1H, dd, J¼6.6, 2.2 Hz,), 4.40
(1H, dd, J¼9.1, 6.6 Hz, CHN), 3.98 (1H, dd, J¼9.1, 2.2 Hz, CH2O), 2.53
(1H, q, J¼7.1 Hz, CH3CH), 1.97 (3H, s, C(CH3)2), 1.66 (3H, s, C(CH3)2),
0.96 (3H, s, CH3COH), 0.88 (3H, d, J¼7.1 Hz, CH3CH); 13C NMR
D
(C]O), 1458, 1423, 1377, 1303, 1205, 1065 cmꢃ1; 1H NMR (360 MHz,
CDCl3) 7.52–7.48 (2H, m, ArH), 7.46–7.41 (3H, m, ArH), 7.03–7.01
d
(2H, m, ArH), 6.82 (2H, d, J¼7.9 Hz, ArH), 5.43 (1H, s, OH), 4.77 (1H,
dd, J¼6.6, 2.2 Hz, CH2O), 4.40 (1H, dd, J¼9.1, 6.6 Hz, CHN), 3.98 (1H,
dd, J¼9.1, 2.2 Hz, CH2O), 2.58 (1H, q, J¼7.1 Hz, CH3CH), 2.29 (3H, s,
ArCH3), 1.98 (3H, s, C(CH3)2), 1.67 (3H, s, C(CH3)2), 0.98 (3H, s,
CH3COH), 0.90 (3H, d, J¼7.1 Hz, CH3CH); 13C NMR (62.9 MHz, CDCl3)
(62.9 MHz, CDCl3)
d
175.9 (C), 144.9 (C), 141.9 (C), 130.8 (2ꢂCH),
129.2 (2ꢂCH), 128.6 (CH), 126.7 (2ꢂCH), 126.5 (2ꢂCH), 120.1 (C),
96.3 (C), 74.4 (C), 71.0 (CH2), 61.6 (CH), 46.5 (CH), 29.4 (CH3), 25.6
(CH3), 22.7 (CH3), 12.1 (CH3); HRMS (ES) exact mass calcd for
79
d
176.3 (C), 142.9 (C), 142.0 (C), 135.6 (C), 129.1 (2ꢂCH), 128.5
C
H
BrNO3 [MþH]þ: 432.1169, found: 432.1168.
22 27
(3ꢂCH), 126.7 (2ꢂCH), 124.4 (2ꢂCH), 96.2 (C), 74.6 (C), 71.0 (CH2),
61.6 (CH), 46.7 (CH), 29.7 (CH3), 25.6 (CH3), 22.7 (CH3), 20.9 (CH3),
12.2 (CH3); HRMS (ES) exact mass calcd for C23H30NO3 [MþH]þ:
368.2220, found: 368.2218.
4.3.6. (4R)-3-[(2R,3R)-3-(4-Bromophenyl)-3-hydroxy-2-
methylbutanoyl]-2,2-dimethyl-4-phenyloxazolidine (23f)
The title compound was prepared according to general pro-
cedure B from 30-chloroacetophenone (143
mL, 1.10 mmol) for a re-
4.3.3. (4R)-3-[(2R,3R)-3-Hydroxy-2-methyl-3-(3-methyl-
phenyl)butanoyl]-2,2-dimethyl-4-phenyloxazolidine (23c)
The title compound was prepared according to general pro-
action time of 17 h and purified by column chromatography (5%
21
EtOAc/petrol) to give a colourless oil (225 mg, 58%). [
1.00, CHCl3); IR (CHCl3) 3418 (OH), 2981, 2934, 2877, 1627 (C]O),
1419, 1205, 1066, 842, 701 cmꢃ1 1H NMR (360 MHz, CDCl3)
a
]
D
ꢃ162 (c
cedure B from 30-methylacetophenone (150
mL, 1.10 mmol) for
;

R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
7737
d
7.54–7.49 (2H, m, ArH), 7.48–7.42 (3H, m, ArH), 7.15–7.10 (2H, m,
OCH3), 2.67 (1H, q, J¼7.1 Hz, CH3CH), 2.00 (3H, s, C(CH3)2), 1.67 (3H,
s, C(CH3)2), 1.65–1.55 (1H, m, CH2CH3), 0.96–0.85 (1H, m, CH2CH3),
0.90 (3H, d, J¼7.1 Hz, CH3CH), 0.43 (3H, t, J¼7.3 Hz, CH2CH3); 13C
ArH), 6.89–6.83 (2H, m, ArH), 5.45 (1H, s, OH), 4.75 (1H, dd, J¼6.7,
2.2 Hz, CH2O), 4.40 (1H, dd, J¼9.1, 6.7 Hz, CHN), 3.99 (1H, dd, J¼9.1,
2.2 Hz, CH2O), 2.58 (1H, q, J¼7.1 Hz, CH3CH), 1.97 (3H, s, C(CH3)2),
1.66 (3H, s, C(CH3)2), 0.93 (3H, s, CH3COH), 0.89 (3H, d, J¼7.1 Hz,
NMR (62.9 MHz, CDCl3)
d 176.5 (C), 157.3 (C), 142.1 (C), 138.6 (C),
132.9 (C), 129.5 (CH), 129.2 (2ꢂCH), 128.5 (CH and C), 126.7 (2ꢂCH),
126.2 (CH), 124.5 (CH), 123.7 (CH), 118.5 (CH), 105.3 (CH), 96.2 (C),
77.9 (C), 71.0 (CH2), 61.6 (CH), 55.2 (CH3), 46.8 (CH), 33.3 (CH2), 25.7
(CH3), 22.6 (CH3), 12.3 (CH3), 7.7 (CH3); HRMS (ES) exact mass calcd
for C28H34NO4 [MþH]þ: 448.2483, found: 448.2490.
CH3CH); 13C NMR (62.9 MHz, CDCl3)
d 175.8 (C), 148.0 (C), 141.9 (C),
133.9 (C), 129.3 (2ꢂCH), 129.1 (CH), 128.6 (CH), 126.7 (2ꢂCH), 126.3
(CH), 1245.0 (CH), 122.7 (CH), 96.2 (C), 74.4 (C), 70.9 (CH2), 61.7
(CH), 46.5 (CH), 29.4 (CH3), 25.5 (CH3), 22.7 (CH3), 12.1 (CH3); HRMS
(ES) exact mass calcd for C
388.1675.
H
ClNO3 [MþH]þ: 388.1675, found:
35
22 27
4.4. Cobalt-catalysed reductive aldol reactions of N-
alkenoyloxazolidines 24a–24h with acetophenone
4.3.7. (4R)-3-[(2R,3R)-3-Hydroxy-2-methyl-3-(naphthalen-2-
yl)butanoyl]-2,2-dimethyl-4-phenyloxazolidine (23g)
4.4.1. Using Co(acac)2$2H2O/Et2Zn: general procedure C
The title compound was prepared according to general pro-
cedure B from 20-acetonaphthone (187 mg, 1.10 mmol) for a re-
action time of 16 h and purified by column chromatography (5%
A
solution of the appropriate N-alkenoyloxazolidine
(0.50 mmol), acetophenone (65 L, 0.55 mmol) and Co(acac)2$
m
2H2O (6.4 mg, 0.025 mmol) in THF (2.5 mL) was stirred at room
temperature for 10 min. The mixture was cooled to 0 ꢁC and Et2Zn
(1 M solution in hexane, 1.00 mL, 1.00 mmol) was then added
dropwise over 1 min. The reaction was stirred at 0 ꢁC for 15 min and
then at room temperature until complete consumption of the N-
alkenoyloxazolidine as observed by TLC analysis. The reaction
mixture was filtered through a short plug of SiO2 using EtOAc as
eluent (ca. 50 mL) and the filtrate was concentrated in vacuo. Pu-
rification of the residue by column chromatography afforded the
aldol product.
EtOAc/petrol) to give a white solid (302 mg, 75%). Mp 215–217 ꢁC;
21
[
a]
ꢃ11.2 (c 1.00, CHCl3); IR (CHCl3) 3410 (OH), 2980, 2933, 2878,
D
1624 (C]O), 1456, 1418, 1377, 1299, 1065 cmꢃ1; 1H NMR (360 MHz,
CDCl3)
d
7.78–7.76 (2H, m, ArH), 7.67 (1H, d, J¼8.7 Hz, ArH), 7.61–
7.40 (8H, m, ArH), 6.86–6.84 (1H, m, ArH), 5.59 (1H, br s, OH), 4.80
(1H, dd, J¼6.6, 2.2 Hz, CH2O), 4.42 (1H, dd, J¼9.1, 6.6 Hz, CHN), 4.01
(1H, dd, J¼9.1, 2.2 Hz, CH2O), 2.74 (1H, q, J¼7.1 Hz, CH3CH), 2.02 (3H,
s, C(CH3)2), 1.69 (3H, s, C(CH3)2), 1.09 (3H, s, CH3COH), 0.91 (3H, d,
J¼7.1 Hz, CH3CH); 13C NMR (62.9 MHz, CDCl3)
d 176.2 (C), 143.2 (C),
142.1 (C), 133.1 (C), 132.0 (C), 129.3 (2ꢂCH), 128.6 (CH), 128.1 (CH),
127.4 (CH), 127.3 (CH), 126.8 (2ꢂCH), 125.8 (CH), 125.4 (CH), 123.5
(CH), 122.8 (CH), 96.3 (C), 74.9 (C), 71.0 (CH2), 61.7 (CH), 46.6 (CH),
29.6 (CH3), 25.6 (CH3), 22.7 (CH3), 12.2 (CH3); HRMS (ES) exact mass
calcd for C26H30NO3 [MþH]þ: 404.2220, found: 404.2221.
4.4.2. Using CoCl2/Cy2PPh/Et2Zn: general procedure D
A
solution of the appropriate N-alkenoyloxazolidine
(0.50 mmol), the acetophenone (65 L, 0.55 mmol), CoCl2 (3.2 mg,
m
0.025 mmol) and Cy2PPh (7.5 mg, 0.0275 mmol) in THF (2.5 mL)
was stirred at room temperature for 10 min. The mixture was
cooled to 0 ꢁC and Et2Zn (1 M solution in hexane, 1.00 mL,
1.00 mmol) was then added dropwise over 1 min. The reaction was
stirred at 0 ꢁC for 15 min and then at room temperature until
complete consumption of the N-alkenoyloxazolidine as observed
by TLC analysis. The reaction mixture was filtered through a short
plug of SiO2 using EtOAc as eluent (ca. 50 mL) and the filtrate was
concentrated in vacuo. Purification of the residue by column
chromatography afforded the aldol product.
4.3.8. (4R)-3-[(2R,3R)-3-Hydroxy-2-methyl-3-(thiophen-2-
yl)butanoyl]-2,2-dimethyl-4-phenyloxazolidine (23h)
The title compound was prepared according to general pro-
cedure B from 2-acetylthiophene (119 mL, 1.10 mmol) for a reaction
time of 16 h and purified by column chromatography (20% EtOAc/
petrol) followed by recrystallisation from CH2Cl22/1hexane to give
a white solid (220 mg, 61%). Mp 143–145 ꢁC; [
a
]
ꢃ11.8 (c 1.00,
D
CHCl3); IR (CHCl3) 3399 (OH), 2983, 2933, 2878, 1625 (C]O), 1422,
1237, 1066, 844, 702 cmꢃ1 1H NMR (360 MHz, CDCl3)
;
d
7.50–7.39
(5H, m, ArH), 7.09 (1H, dd, J¼5.1, 1.2 Hz, CH), 6.86 (1H, dd, J¼5.1,
3.5 Hz, CH), 6.35 (1H, dd, J¼3.5, 1.2 Hz, CH), 5.57 (1H, s, OH), 4.76
(1H, dd, J¼6.6, 2.1 Hz, CH2O), 4.40 (1H, dd, J¼9.1, 6.6 Hz, CHN), 3.99
(1H, dd, J¼9.1, 2.1 Hz, CH2O), 2.60 (1H, q, J¼7.1 Hz, CH3CH), 1.96 (3H,
s, C(CH3)2), 1.65 (3H, s, C(CH3)2), 1.04 (3H, d, J¼7.1 Hz, CH3CH), 1.00
4.4.3. (4R)-3-[(2R,3R)-2-Ethyl-3-hydroxy-3-phenylbutanoyl]-2,2-
dimethyl-4-phenyloxazolidine (25a)
The title compound was prepared according to general pro-
cedure D from N-alkenoyloxazolidine 24a (123 mg, 0.50 mmol) for
a reaction time of 14 h and purified by column chromatography
(3H, s, CH3COH); 13C NMR (62.9 MHz, CDCl3)
d
175.8 (C), 151.0 (C),
(10% EtOAc/hexane) to give a white solid (150 mg, 82%). Mp 131–
21
141.8 (C), 129.1 (2ꢂCH), 128.4 (CH), 126.6 (2ꢂCH), 126.5 (CH), 123.1
(CH), 121.0 (CH), 96.2 (C), 74.7 (C), 70.9 (CH2), 61.5 (CH), 47.7 (CH),
30.6 (CH3), 25.5 (CH3), 22.6 (CH3), 12.4 (CH3); HRMS (ES) exact mass
calcd for C20H26NO3S [MþH]þ: 360.1628, found: 360.1637.
133 ꢁC; [
a]
ꢃ226 (c 1.00, CHCl3); IR (CHCl3) 3387 (OH), 2973, 1620
D
(C]O), 1457, 1408, 1308, 1133, 1067, 766, 703 cmꢃ1
;
1H NMR
(360 MHz, CDCl3) 7.54–7.42 (5H, m, ArH), 7.24–7.13 (3H, m, ArH),
d
6.98 (2H, d, J¼7.3 Hz, ArH), 5.33 (1H, s, OH), 4.94 (1H, dd, J¼6.6,
1.6 Hz, CH2O), 4.41 (1H, dd, J¼9.1, 6.6 Hz, CHN), 4.00 (1H, dd, J¼9.1,
1.6 Hz, CH2O), 2.67 (1H, dd, J¼10.8, 4.0 Hz, CHC]O), 2.01 (3H, s,
C(CH3)2), 1.87–1.74 (1H, m, CH2CH3), 1.72 (3H, s, C(CH3)2), 1.21–1.10
(1H, m, CH2CH3), 0.87 (3H, t, J¼6.6 Hz, CH2CH3), 0.78 (3H, s,
4.3.9. (4R)-3-[(2R,3R)-3-Hydroxy-2-methyl-3-(6-methoxy-
naphthalen-2-yl)pentanoyl]-2,2-dimethyl-4-phenyl-
oxazolidine (23j)
The title compound was prepared according to general pro-
CH3COH); 13C NMR (62.9 MHz, CDCl3)
d 175.7 (C), 146.1 (C), 142.0
cedure
B
from 60-methoxy-20-propiononaphthone (236 mg,
(C), 129.1 (2ꢂCH), 128.6 (CH), 127.7 (2ꢂCH), 127.4 (2ꢂCH), 126.1
(CH), 124.6 (2ꢂCH), 96.6 (C), 74.9 (C), 70.8 (CH2), 61.9 (CH), 53.6
(CH), 29.8 (CH3), 25.7 (CH3), 22.6 (CH3), 21.7 (CH2), 12.1 (CH3);
HRMS (ES) exact mass calcd for C23H30NO3 [MþH]þ: 368.2220,
found: 368.2221.
1.10 mmol) for a reaction time of 3 h and purified by column
chromatography (20% EtOAc/petrol) followed by recrystallisation
from CH2Cl2/hexane to give a white solid (265 mg, 59%). Mp 164–
21
166 ꢁC; [
a]
ꢃ3.9 (c 1.00, CHCl3); IR (CHCl3) 3388 (OH), 2975, 2935,
D
2877, 1623 (C]O), 1417, 1266, 1173, 1067, 703 cmꢃ1
;
1H NMR
(360 MHz, CDCl3)
d
7.66 (1H, d, J¼8.8 Hz, ArH), 7.58–7.45 (7H, m,
4.4.4. (4R)-3-[(2R,3R)-2-iso-Butyl-3-hydroxy-3-phenylbutanoyl]-
2,2-dimethyl-4-phenyloxazolidine (25b)
The title compound was prepared according to general pro-
cedure D from N-alkenoyloxazolidine 24b (137 mg, 0.50 mmol) for
ArH), 7.12 (1H, dd, J¼8.9, 5.6 Hz, ArH), 7.08 (1H, d, J¼2.5 Hz, ArH),
5.21 (1H, s, OH), 4.79 (1H, dd, J¼6.6, 2.1 Hz, CH2O), 4.41 (1H, dd,
J¼9.1, 6.6 Hz, CHN), 3.99 (1H, dd, J¼9.1, 2.1 Hz, CH2O), 3.91 (3H, s,

7738
R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
21
a reaction time of 14 h and purified by column chromatography
[a
]
ꢃ304 (c 1.00, CHCl3); IR (CHCl3) 3386 (OH), 3027, 1618 (C]O),
D
(10% EtOAc/hexane) to give a white solid (156 mg, 79%). Mp 195–
1511, 1456, 1418, 1109, 1066, 768, 703 cmꢃ1
CDCl3) 7.52–7.41 (3H, m, ArH), 7.36–7.22 (5H, m, ArH), 7.07–7.05
;
1H NMR (360 MHz,
21
197 ꢁC; [
a]
ꢃ182 (c 1.00, CHCl3); IR (CHCl3) 3346 (OH), 2954, 1612
d
D
(C]O), 1456, 1409, 1303, 1130, 1067, 768, 705 cmꢃ1
;
1H NMR
(2H, m, ArH), 7.02 (2H, d, J¼8.6 Hz, ArH), 6.90 (2H, d, J¼8.6 Hz, ArH),
5.56 (1H, s, OH), 3.83 (3H, s, OCH3), 3.75 (1H, dd, J¼9.0, 6.5 Hz, CHN),
3.65 (1H, dd, J¼9.0, 1.1 Hz, CH2O), 3.47 (1H, app d, J¼5.8 Hz, CH2O),
3.00 (1H, dd, J¼13.1, 11.9 Hz, CHC]O), 2.88 (1H, dd, J¼11.9, 2.4 Hz,
CH2Ar), 2.36 (1H, dd, J¼13.1, 2.4 Hz, CH2Ar), 1.98 (3H, s, C(CH3)2),
1.66 (3H, s, C(CH3)2), 0.91 (3H, s, CH3COH); 13C NMR (62.9 MHz,
(360 MHz, CDCl3) 7.54–7.41 (5H, m, ArH), 7.23–7.11 (3H, m, ArH),
d
6.97 (2H, d, J¼7.3 Hz, ArH), 5.25 (1H, s, OH), 4.90 (1H, dd, J¼6.6,
1.6 Hz, CH2O), 4.41 (1H, dd, J¼9.1, 6.6 Hz, CHN), 4.00 (1H, dd, J¼9.1,
1.6 Hz, CH2O), 2.74 (1H, dd, J¼10.1, 3.2 Hz, CHC]O), 2.01 (3H, s,
C(CH3)2), 1.76–1.67 (1H, m, CH2CH(CH3)2), 1.61 (3H, s, C(CH3)2),
1.32–1.20 (1H, m, CH(CH3)2), 1.04 (1H, ddd, J¼14.1, 9.5, 3.2 Hz,
CH2CH(CH3)2), 0.82 (3H, d, J¼6.5 Hz, CH(CH3)2), 0.77 (3H, s,
CH3COH), 0.75 (3H, d, J¼6.5 Hz, CH(CH3)2); 13C NMR (62.9 MHz,
CDCl3)
d 174.0 (C), 158.4 (C), 146.0 (C), 142.1 (C), 131.9 (C), 130.0
(2ꢂCH), 128.9 (2ꢂCH), 128.3 (CH), 127.9 (2ꢂCH), 127.0 (2ꢂCH),
126.2 (CH), 124.4 (2ꢂCH), 113.8 (2ꢂCH), 96.2 (C), 75.2 (C), 70.4
(CH2), 60.6 (CH), 55.7 (CH), 55.2 (CH3), 34.0 (CH2), 29.7 (CH3), 25.4
(CH3), 22.2 (CH3); HRMS (ES) exact mass calcd for C29H34NO4
[MþH]þ: 460.2482, found: 460.2482.
CDCl3)
d
176.3 (C), 146.1 (C), 141.9 (C), 129.2 (2ꢂCH), 128.6 (CH),
127.7 (2ꢂCH), 127.2 (2ꢂCH), 126.1 (CH), 124.5 (2ꢂCH), 96.6 (C), 75.3
(C), 70.9 (CH2), 61.6 (CH), 50.6 (CH), 38.5 (CH2), 30.2 (CH3), 26.0
(CH), 25.6 (CH3), 23.9 (CH3), 22.7 (CH3), 22.6 (CH3); HRMS (ES) exact
mass calcd for C25H34NO3 [MþH]þ: 396.2533, found: 396.2534.
4.4.8. (4R)-3-[(2R,3R)-2-(4-Chlorobenzyl)-3-hydroxy-3-
phenylbutanoyl]-2,2-dimethyl-4-phenyloxazolidine (25f)
4.4.5. (4R)-3-[(2R,3R)-3-Hydroxy-3-phenylbutanoyl-2-(3-
phenylpropyl)]-2,2-dimethyl-4-phenyloxazolidine (25c)
The title compound was prepared according to general pro-
cedure D from N-alkenoyloxazolidine 24c (168 mg, 0.50 mmol) for
a reaction time of 14 h and purified by column chromatography
The title compound was prepared according to general pro-
cedure C from N-alkenoyloxazolidine 24f (171 mg, 0.50 mmol) for
a reaction time of 6 h and purified by column chromatography
(10% EtOAc/hexane) to give a white solid (194 mg, 84%). Slow
evaporation of a CDCl3 solution of 25f was found to give colourless
21
(10% EtOAc/hexane) to give a white solid (182 mg, 80%). Mp 130–
crystals suitable for X-ray diffraction. Mp 139–140 ꢁC; [
a]
ꢃ304
D
21
132 ꢁC; [
a]
ꢃ190 (c 1.00, CHCl3); IR (CHCl3) 3398 (OH), 3028, 1619
(c 1.00, CHCl3); IR (CHCl3) 3398 (OH), 3027, 1627 (C]O), 1493,
1423, 1313, 1296, 910, 767, 702 cmꢃ1 1H NMR (360 MHz, CDCl3)
7.53–7.43 (3H, m, ArH), 7.36–7.23 (7H, m, ArH), 7.04 (4H, dm,
D
(C]O), 1427, 1397, 1066, 1053, 837, 740, 706 cmꢃ1
;
1H NMR
;
(360 MHz, CDCl3) 7.59–7.48 (5H, m, ArH), 7.34–7.22 (6H, m, ArH),
d
d
7.11 (2H, d, J¼7.2 Hz, ArH), 7.06 (2H, d, J¼7.2 Hz, ArH), 5.41 (1H, s,
OH), 4.86 (1H, dd, J¼6.5, 1.5 Hz, CH2O), 4.37 (1H, dd, J¼9.1, 6.5 Hz,
CHN), 4.01 (1H, dd, J¼9.1, 1.5 Hz, CH2O), 2.77 (1H, dd, J¼9.9, 4.0 Hz,
CHC]O), 2.52 (2H, t, J¼7.2 Hz, CH2Ar), 2.07 (3H, s, C(CH3)2), 1.94–
1.82 (1H, m, CHCH2CH2), 1.76 (3H, s, C(CH3)2), 1.69–1.56 (1H, m,
CHCH2CH2), 1.50–1.31 (2H, m, CH2CH2CH2), 0.89 (3H, s, CH3COH);
J¼8.4 Hz, ArH), 5.46 (1H, s, OH), 3.76 (1H, dd, J¼9.1, 6.5 Hz, CHN),
3.68 (1H, dd, J¼9.1, 1.3 Hz, CH2O), 3.48 (1H, dd, J¼6.5, 1.3 Hz,
CH2O), 3.00 (1H, dd, J¼13.1, 11.9 Hz, CHC]O), 2.88 (1H, dd, J¼11.9,
2.7 Hz, CH2Ar), 2.37 (1H, dd, J¼13.1, 2.7 Hz, CH2Ar), 1.98 (3H, s,
C(CH3)2), 1.62 (3H, s, C(CH3)2), 0.89 (3H, s, CH3COH); 13C NMR
(62.9 MHz, CDCl3)
d 174.6 (C), 145.8 (C), 141.9 (C), 138.5 (C), 132.5
13C NMR (62.9 MHz, CDCl3)
d
175.6 (C), 146.0 (C), 141.9 (C), 141.8 (C),
(C), 130.5 (2ꢂCH), 129.0 (2ꢂCH), 128.5 (4ꢂCH), 128.0 (2ꢂCH), 127.1
129.1 (2ꢂCH), 128.5 (CH), 128.3 (2ꢂCH), 128.1 (2ꢂCH), 127.7
(2ꢂCH), 127.2 (2ꢂCH), 126.1 (CH), 125.7 (CH), 124.6 (2ꢂCH), 96.5
(C), 74.8 (C), 70.8 (CH2), 61.7 (CH), 52.3 (CH), 36.2 (CH2), 29.8 (CH3
and CH2), 28.4 (CH2), 25.6 (CH3), 22.5 (CH3); HRMS (FAB) exact mass
calcd for C30H36NO3 [MþH]þ: 458.2690, found: 458.2687.
(2ꢂCH), 126.4 (CH), 124.5 (CH), 96.4 (C), 75.2 (C), 70.4 (CH2), 60.8
(CH), 55.4 (CH), 34.2 (CH2), 29.6 (CH3), 25.5 (CH3), 22.2 (CH3);
35
HRMS (ES) exact mass calcd for C
found: 464.1990.
H
ClNO3 [MþH]þ: 464.1987,
28 31
4.4.9. (4R)-3-[(2R,3R)-3-Hydroxy-2-(naphthalen-2-ylmethyl)-3-
phenylbutanoyl]-2,2-dimethyl-4-phenyloxazolidine (25g)
The title compound was prepared according to general pro-
cedure C from N-alkenoyloxazolidine 24g (179 mg, 0.50 mmol) for
a reaction time of 16 h and purified by column chromatography
4.4.6. (4R)-3-[(2R,3R)-2-Benzyl-3-hydroxy-3-phenylbutanoyl]-2,2-
dimethyl-4-phenyloxazolidine (25d)
The title compound was prepared according to general pro-
cedure C from N-alkenoyloxazolidine 24d (154 mg, 0.50 mmol) for
a reaction time of 4 h and purified by column chromatography (10%
(10% EtOAc/hexane) to give a white solid (216 mg, 90%). Mp 136–
21
EtOAc/hexane) to give a white solid (184 mg, 86%). Mp 139–141 ꢁC;
138 ꢁC; [
a
]
D
ꢃ358 (c 1.00, CHCl3); IR (CHCl3) 3389 (OH), 3026, 1620
[
a]
ꢃ286 (c 1.00, CHCl3); IR (CHCl3) 3387 (OH), 3026, 1620 (C]O),
(C]O), 1420, 1302, 1249, 1067, 908, 733, 703 cmꢃ1
(360 MHz, CDCl3)
;
1H NMR
7.94–7.88 (2H, m, ArH), 7.85 (2H, d, J¼8.6 Hz,
21
D
1455, 1421, 1301, 1249, 1065, 843, 702 cmꢃ1
;
1H NMR (360 MHz,
d
CDCl3) 7.52–7.41 (3H, m, ArH), 7.39–7.24 (8H, m, ArH), 7.14–7.09
d
ArH), 7.61–7.51 (5H, m, ArH), 7.38–7.29 (5H, m, ArH), 7.14–7.11 (2H,
m, ArH), 6.99 (1H, br s, ArH), 5.72 (1H, s, OH), 3.73 (1H, dd, J¼9.0,
6.4 Hz, CHN), 3.66 (1H, dd, J¼9.0, 1.1 Hz, CH2O), 3.38 (1H, app d,
J¼5.9 Hz, CH2O), 3.15 (1H, dd, J¼12.6, 12.0 Hz, CHC]O), 3.06 (1H,
dd, J¼12.0, 1.8 Hz, CH2Ar), 2.48 (1H, dd, J¼12.6, 1.8 Hz, CH2Ar), 2.05
(3H, s, C(CH3)2), 1.71 (3H, s, C(CH3)2), 1.07 (3H, s, CH3COH); 13C NMR
(4H, m, ArH), 5.56 (1H, s, OH), 3.68 (1H, dd, J¼9.0, 6.4 Hz, CHN), 3.62
(1H, dd, J¼9.0, 1.3 Hz, CH2O), 3.35 (1H, app d, J¼5.4 Hz, CH2O), 3.05
(1H, app t, J¼12.5 Hz, CHC]O), 2.90 (1H, dd, J¼11.9, 2.6 Hz, CH2Ph),
2.43 (1H, dd, J¼13.0, 2.6 Hz, CH2Ph),1.98 (3H, s, C(CH3)2),1.65 (3H, s,
C(CH3)2), 0.92 (3H, s, CH3COH); 13C NMR (62.9 MHz, CDCl3)
d 174.9
(C), 146.0 (C), 142.1 (C), 140.0 (C), 129.1 (2ꢂCH), 128.9 (2ꢂCH), 128.5
(2ꢂCH), 128.3 (CH), 127.9 (2ꢂCH), 127.0 (2ꢂCH), 126.7 (CH), 126.3
(CH), 124.5 (2ꢂCH), 96.3 (C), 75.3 (C), 70.4 (CH2), 60.5 (CH), 55.7
(CH), 34.9 (CH2), 29.7 (CH3), 25.5 (CH3), 22.1 (CH3); HRMS (ES) exact
mass calcd for C28H32NO3 [MþH]þ: 430.2377, found: 430.2382.
(62.9 MHz, CDCl3) d 174.9 (C), 143.2 (C), 142.2 (C), 139.9 (C), 133.1
(C), 132.1 (C), 129.1 (2ꢂCH), 129.0 (2ꢂCH), 128.4 (3ꢂCH), 128.1 (CH),
127.6 (CH), 127.3 (CH), 127.1 (2ꢂCH), 126.7 (CH), 125.9 (CH), 125.5
(CH), 123.6 (CH), 122.7 (CH), 96.3 (C), 75.5 (C), 70.4 (CH2), 60.5 (CH),
55.5 (CH), 35.0 (CH2), 29.7 (CH3), 25.5 (CH3), 22.1 (CH3); HRMS (ES)
Exact mass calcd for
480.2539.
C
32H34NO3 [MþH]þ: 480.2533, found:
4.4.7. (4R)-3-[(2R,3R)-3-Hydroxy-2-(4-methoxybenzyl)-3-
phenylbutanoyl]-2,2-dimethyl-4-phenyloxazolidine (25e)
The title compound was prepared according to general pro-
cedure C from N-alkenoyloxazolidine 24e (169 mg, 0.50 mmol) for
a reaction time of 6 h and purified by column chromatography (10%
EtOAc/hexane) to give a white solid (198 mg, 86%). Mp 115–117 ꢁC;
4.4.10. (4R)-3-[(2R,3R)-2-(Furan-2-ylmethyl)-3-hydroxy-3-
phenylbutanoyl]-2,2-dimethyl-4-phenyloxazolidine (25h)
The title compound was prepared according to general pro-
cedure C from N-alkenoyloxazolidine 24h (149 mg, 0.50 mmol) for

R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
7739
a reaction time of 4 h and purified by column chromatography (10%
Supplementary data
EtOAc/hexane) to give a white solid (174 mg, 83%). Mp 96–98 ꢁC;
21
[
a]
ꢃ298 (c 1.00, CHCl3); IR (CHCl3) 3378 (OH), 3028, 1622 (C]O),
Copies of 1H and 13C NMR spectra for new compounds in Tables
4 and 5 and Eq. 2. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2008.06.022.
D
1456, 1378, 1066, 1013, 914, 767, 702 cmꢃ1
;
1H NMR (360 MHz,
CDCl3) 7.55–7.51 (2H, m, ArH), 7.47–7.43 (4H, m, ArH), 7.33–7.29
d
(2H, m, ArH), 7.25–7.21 (1H, m, ArH) 7.09–7.07 (2H, m, ArH, CH),
6.38 (1H, dd, J¼3.2, 1.9 Hz, CH), 6.03 (1H, d, J¼3.2 Hz, CH), 5.56 (1H,
s, OH), 4.00 (1H, dd, J¼8.8, 6.5 Hz, CH2N), 3.87 (1H, dd, J¼6.5, 1.2 Hz,
CH2O), 3.82 (1H, dd, J¼8.8, 1.2 Hz, CH2O), 3.13 (1H, dd, J¼13.1,
11.8 Hz, CHC]O), 3.07 (1H, dd, J¼11.8, 1.7 Hz, CH2CHC]O), 2.39
(1H, dd, J¼13.1, 1.7 Hz, CH2CH), 1.99 (3H, s, C(CH3)2), 1.61 (3H, s,
References and notes
1. For a seminal reference, see: (a) Revis, A.; Hilty, T.K. Tetrahedron Lett. 1987, 28,
4809–4812; For an extensive collection of reports of catalytic reductive aldol
reactions, see references cited within: (b) Ngai, M.-Y.; Kong, J.-R.; Krische, M.J. J.
Org. Chem. 2006, 72, 1063–1072; For relevant reviews, see: (c) Nishiyama, H.;
Shiomi, T. Top. Curr. Chem. 2007, 279, 105–137; (d) Jang, H.-Y.; Krische, M. J. Eur. J.
Org. Chem. 2004, 3953–3958; (e) Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004,
37, 653–661; (f) Huddleston, R. R.; Krische, M. J. Synlett 2003, 12–21; (g) Chiu, P.
Synthesis 2004, 2210–2215; (h) Motherwell, W. B. Pure Appl. Chem. 2002, 74,
135–142.
2. (a) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 2746–2747; (b) Shiomi, T.; Nishiyama, H. Org. Lett. 2007, 9, 1651–1654; (c)
Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int. Ed. 2006,
45, 1292–1297; (d) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2006, 128, 14440–14441; (e) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 2006, 46, 1403–1407; (f) Nishiyama, H.; Shiomi, T.; Tsuchiya,
Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972–6973; (g) Russell, A. E.; Fuller,
N. O.; Taylor, S. J.; Aurriset, S.; Morken, J. P. Org. Lett. 2004, 6, 2309–2312; (h)
Zhao, C.-X.; Duffey, M. O.; Taylor, S. O.; Morken, J. P. Org. Lett. 2001, 3, 1829–
1831; (i) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000, 122,
4528–4529.
3. (a) Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Prieto, O.;
Luebbers, T. Org. Lett. 2006, 8, 3729–3732; (b) Lumby, R. J. R.; Joensuu, P. M.;
Lam, H. W. Org. Lett. 2007, 9, 4367–4370.
4. Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.; Luebbers, T; Lam, H. W. J. Am.
Chem. Soc. 2008, 130, 7328–7338.
5. For cobalt-catalysed reductive aldol reactions, see: (a) Isayama, S.; Mukaiyama,
T. Chem. Lett. 1989, 2005–2008; (b) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.;
Schultz, A. J.; Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448–9453.
6. (a) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225–4228; (b) Lam, H. W.;
Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743–5746.
7. The relative stereochemistry of the known compound 4a was assigned by
comparison with literature spectral data. See: Taniguchi, M.; Hideaki, F.;
Koichiro, O.; Kiitiro, U. Tetrahedron Lett. 1992, 33, 4353–4356.
C(CH3)2), 0.89 (3H, s, CH3COH); 13C NMR (62.9 MHz, CDCl3)
d 174.6
(C), 153.7 (C), 145.4 (C), 142.3 (C), 141.0 (CH), 129.0 (2ꢂCH), 128.4
(CH), 127.9 (2ꢂCH), 127.2 (2ꢂCH), 126.4 (CH), 124.5 (2ꢂCH), 110.9
(CH), 107.1 (CH), 96.3 (C), 74.8 (C), 70.6 (CH2), 60.7 (CH), 52.4 (CH),
29.7 (CH3), 26.8 (CH2), 25.5 (CH3), 22.1 (CH3); HRMS (ES) exact mass
calcd for C26H30NO4 [MþH]þ: 420.2169, found: 420.2171.
4.4.11. (4R)-3-[(2R,3R)-2-Benzyl-3-hydroxy-3-(naphthalen-2-
yl)butanoyl]-2,2-dimethyl-4-phenyloxazolidine (26)
On a 0.50 mmol scale: a solution of N-alkenoyloxazolidine 24d
(154 mg, 0.50 mmol), 20-acetonaphthone (94 mg, 0.55 mmol) and
Co(acac)2$2H2O (6.4 mg, 0.025 mmol) in THF (2.5 mL) was stirred at
room temperature for 10 min. The mixture was cooled to 0 ꢁC and
Et2Zn (1 M solution in hexane, 1.00 mL, 1.00 mmol) was then added
dropwise over 1 min. The reaction was stirred at 0 ꢁC for 15 min and
then at room temperature for 6 h. The reaction mixture was filtered
through a short plug of SiO2 using EtOAc as eluent (ca. 50 mL) and
the filtrate was concentrated in vacuo. Purification of the residue by
column chromatography (10% EtOAc/hexane) gave the aldol product
26 (218 mg, 91%) as a white solid.
On a 5.00 mmol scale: a solution of N-alkenoyloxazolidine 24d
(1.54 g, 5.00 mmol), 20-acetonaphthone (936 mg, 5.50 mmol) and
Co(acac)2$2H2O (64 mg, 0.25 mmol) in THF (25 mL) was stirred at
room temperature for 10 min. The mixture was cooled to 0 ꢁC and
Et2Zn (1 M solution in hexane, 10.0 mL, 10.0 mmol) was then added
over 1 min. The reaction was stirred at 0 ꢁC for 15 min and then at
room temperature for 16 h. The reaction was quenched carefully
with saturated aqueous NH4Cl solution (20 mL), and the mixture
was extracted with CH2Cl2 (3ꢂ15 mL). Purification of the residue by
8. Crystallographic data (excluding structure factors) for products 4c, 7f and 7g
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 666641–666643. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
9. For initial, speculative proposals about the mechanism of cobalt-catalysed
conjugate reduction of a,b-unsaturated amides in the presence of diethylzinc,
see Ref. 3a. Figure 1 presents a revised model.
10. (a) Johnson, J. R.; Tully, P. S.; MacKenzie, P. B.; Sabat, M. J. Am. Chem. Soc. 1991,
113, 6172–6177; (b) Grisso, B. A.; Johnson, J. R.; MacKenzie, P. B. J. Am. Chem. Soc.
1992, 114, 5160–5165.
11. (a) Ogoshi, S.; Yoshida, T.; Nishida, T.; Morita, M.; Kurosawa, H. J. Am. Chem. Soc.
2001, 123, 1944–1950; (b) Ogoshi, S.; Tomiyasu, S.; Morita, M.; Kurosawa, H.
J. Am. Chem. Soc. 2002, 124, 11598–11599.
12. Hratchian, H. P.; Chowdhury, S. K.; Gutierrez-Garcıa, V. M.; Amarasinghe, K. K.
D.; Heeg, M. J.; Schlegel, H. B.; Montgomery, J. Organometallics 2004, 23, 4636–
4646.
13. Jonas, K.; Koepe, G.; Krueger, C. Angew. Chem., Int. Ed. Engl. 1986, 25, 923–925.
14. (a) Kaschube, W.; Po¨rschke, K.-R.; Angermund, K.; Kru¨ger, C.; Wilke, G. Chem.
Ber. 1988, 121, 1921–1929; (b) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am.
Chem. Soc. 2005, 127, 12810–12811.
15. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–1923.
16. (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23–32; (b) Heathcock, C. H. Com-
prehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 2, p 181; (c) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917–947; (d)
Palomo, C.; Oiarbide, M.; Garcı´a, J. M. Chem.dEur. J. 2002, 8, 36–44.
17. For chiral auxiliary-controlled asymmetric ketone aldol reactions, see: (a)
Ojima, I.; Yoshida, K.; Inaba, S.-i. Chem. Lett. 1977, 429–432; (b) Sakito, Y.; Asami,
M.; Mukaiyama, T. Chem. Lett. 1980, 455–458; (c) Basavaiah, D.; Bharathi, T. K.
Tetrahedron Lett. 1991, 28, 3417–3420; (d) Akiyama, T.; Ishikawa, K.; Ozaki, S.
Synlett 1994, 275–276; (e) Bartroli, J.; Turmo, E.; Belloc, J.; Forn, J. J. Org. Chem.
1995, 60, 3000–3012; (f) Jacobson, I. C.; Reddy, G. P. Tetrahedron Lett. 1996, 37,
8263–8266; (g) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P. Tetrahedron 1996,
38, 12433–12442; (h) Judge, T. M.; Phillips, G.; Morris, J. K.; Lovasz, K. D.;
Romines, K. R.; Luke, G. P.; Tulinsky, J.; Tustin, J. M.; Chrusciel, R. A.; Dolak, L. A.;
Mizsak, S. A.; Watt, W.; Morris, J.; Vander Velde, S. L.; Strohbach, J. W.; Gammill,
column chromatography (10% EtOAc/hexane) gave the aldol product
21
26 (2.16 g, 90%) as a white solid. Mp 139–141 ꢁC; [
a
]
D
ꢃ374 (c 1.00,
CHCl3); IR (CHCl3) 3389 (OH), 3026, 1622 (C]O), 1455, 1417, 1377,
1066, 909, 768, 702 cmꢃ1 1H NMR (360 MHz, CDCl3)
;
d
7.82–7.76
´
´
(2H, m, ArH), 7.82–7.79 (1H, m, ArH) 7.55–7.13 (12H, m, ArH), 7.07
(2H, br s, ArH), 5.53 (1H, s, OH), 3.35 (1H, app d, J¼8.7 Hz, CH2O),
3.22–3.09 (2H, m, CH2O and CHC]O), 3.17 (1H, dd, J¼8.7, 6.6 Hz,
CH2N), 2.93 (1H, dd, J¼11.9, 2.8 Hz, CH2Ph), 2.52 (1H, dd, J¼13.2,
2.8 Hz, CH2Ph), 1.91 (3H, s, C(CH3)2), 1.53 (3H, s, C(CH3)2), 0.87 (3H,
s, CH3COH); 13C NMR (62.9 MHz, CDCl3)
d
174.9 (C), 145.0 (C), 142.0
(C), 137.3 (C), 133.2 (C), 132.0 (C), 128.9 (2ꢂCH), 128.3 (CH), 128.2
(CH), 128.0 (2ꢂCH), 127.7 (CH), 127.5 (CH), 127.3 (CH), 127.1 (2ꢂCH),
127.0 (CH), 126.5 (CH), 126.4 (CH), 125.6 (CH), 124.5 (2ꢂCH), 96.1
(C), 75.3 (C), 70.1 (CH2), 60.5 (CH), 55.6 (CH), 35.1 (CH2), 29.7 (CH3),
25.5 (CH3), 22.1 (CH3); HRMS (ES) exact mass calcd for C32H34NO3
[MþH]þ: 480.2533, found: 480.2532.
Acknowledgements
This work was supported by the EPSRC, Merck Sharp & Dohme
and the University of Edinburgh. We thank Professor Simon Par-
sons, Dr. Anna Collins, Laura E. Budd, Fraser J. White and Peter A.
Wood at the University of Edinburgh for assistance with X-ray
crystallography. We also thank the EPSRC National Mass Spec-
trometry Service Centre at the University of Wales, Swansea for
providing high resolution mass spectra.
´
R. B. J. Am. Chem. Soc. 1997, 119, 3627–3628; (i) Garcıa Ruano, J. L.; Barros, D.;
Carmen Maestro, M.; Slawin, A. M. Z.; Bulman Page, P. C. J. Org. Chem. 2000, 65,
6027–6034.
18. For catalytic enantioselective aldol reactions of preformed enolates with
ketones, see: (a) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C.
J. Am. Chem. Soc. 1997, 119, 7893–7894; (b) Evans, D. A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 1997, 119, 10859–10860; (c) Evans, D. A.; Burgey, C. S.;

7740
R.J.R. Lumby et al. / Tetrahedron 64 (2008) 7729–7740
Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686–699; (d) Le, J.
Galliford, C. V.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 15566–15567; (d)
Lettan, R. B., II; Woodward, C. C.; Scheidt, K. A. Angew. Chem., Int. Ed. 2008,
47, 2294–2297.
C.-D.; Pagenkopf, B. L. Org. Lett. 2004, 6, 4097–4099; (e) Denmark, S. E.; Fan, Y.;
Eastgate, M. D. J. Org. Chem. 2005, 70, 5235–5248; (f) Moreau, X.; Baza´n-Tejeda,
B.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 7288–7289; (g) Oisaki, K.; Zhao,
D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7164–7165; For a cat-
alytic enantioselective Reformatsky reaction with ketones, see: (h) Cozzi, P. G.
Angew. Chem., Int. Ed. 2006, 45, 2951–2954.
22. The stereochemistries of the minor diastereomers produced in the reactions in
Tables 4 and 5 were not determined.
23. Crystallographic data (excluding structure factors) for products 23a, 23d and
25f have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 634191–634193. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
24. (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996, 37, 3623–
3626; (b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
19. For catalytic enantioselective reductive aldol reactions with ketones, see Refs.
2b–e and 6a.
20. For similar observations in related reactions, see Ref. 3a, and: Chrovian, C. C.;
Montgomery, J. Org. Lett. 2007, 9, 537–540.
21. (a) Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48, 8631–8644; (b) Kane-
masa, S.; Onimura, K. Tetrahedron 1992, 48, 8645–8658; For the use of chiral
oxazolidines in related reactions, see: (c) Lettan, R. B., II; Reynolds, T. E.;
25. Kanemasa, S.; Suenaga, H.; Onimura, K. J. Org. Chem. 1994, 59, 6949–6954.